Abstract

Background
Gene association studies detect an influence of natural variation in the 5-hydroxytryptamine transporter (5-
HTT) gene on multiple aspects of individuality in brain function, ranging from personality traits through to
susceptibility to psychiatric disorders such as anxiety and depression. The neural substrates of these
associations are unknown. Human neuroimaging studies suggest modulation of the amygdala by 5-HTT
variation, but this hypothesis is controversial and unresolved, and difficult to investigate further in humans.
Methods
We used a mouse model in which the 5-HTT is overexpressed throughout the brain and recorded
hemodynamic responses (using a novel in vivo voltammetric monitoring method, analogous to blood
oxygen level–dependent functional magnetic resonance imaging) and local field potentials during
Pavlovian fear conditioning. Results
Increased 5-HTT expression impaired, but did not prevent, fear learning and significantly reduced amygdala hemodynamic responses to aversive cues. Increased 5-HTT expression was also associated with
reduced theta oscillations, which were a feature of aversive cue presentation in controls. Moreover, in
control mice, but not those with high 5-HTT expression, there was a strong correlation between theta
power and the amplitude of the hemodynamic response.
Conclusions
Direct experimental manipulation of 5-HTT expression levels throughout the brain markedly altered fear
learning, amygdala hemodynamic responses, and neuronal oscillations.

Item Type:

Article

Additional Information:

The definitive version of this article is available at DOI: 10.1016/j.biopsych.2013.09.003